Search

PURPOSE KEYNOTE-164 (NCT02460198) evaluated the antitumor activity of pembrolizumab in previously treated, metastatic, microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) colorectal cancer (CRC). METHODS This phase II open-label study involved 128 centers worldwide. Eligible patients were age ≥ 18 years and had metastatic MSI-H/dMMR CRC treated with ≥ 2 prior lines of standard therapy, including fluoropyrimidine, oxaliplatin, and irinotecan with or without anti–vascular endothelial growth factor/epidermal growth factor receptor monoclonal antibody (cohort A) or ≥ 1 prior line of therapy (cohort B). MSI-H/dMMR status was assessed locally. Patients received pembrolizumab 200 mg every 3 weeks for up to 2 years until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate by RECIST version 1.1 by independent central review. Secondary end points were duration of response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS A total of 124 patients with MSI-H/dMMR CRC (61 in cohort A, 63 in cohort B) enrolled. At data cutoff, median follow-up was 31.3 months (range, 0.2-35.6 months) for cohort A and 24.2 months (range, 0.1-27.1 months) for cohort B. Objective response rate was 33% (95% CI, 21% to 46%) and 33% (95% CI, 22% to 46%), respectively, with median duration of response not reached in either cohort. Median PFS was 2.3 months (95% CI, 2.1 to 8.1 months) and 4.1 months (95% CI, 2.1 to 18.9 months). Median overall survival was 31.4 months (95% CI, 21.4 months to not reached) and not reached (95% CI, 19.2 months to not reached). Treatment-related grade 3-4 adverse events occurred in 10 patients (16%) in cohort A and 8 (13%) in cohort B, with the most common occurring in ≥ 2 patients being pancreatitis, fatigue, increased alanine aminotransferase, and increased lipase (2 patients each; 3%) in cohort A. CONCLUSION Pembrolizumab is effective with a manageable safety profile in patients with MSI-H/dMMR CRC.

TPS275 Background: Colorectal cancer (CRC) is the second leading cause of cancer-related death in US. The majority of US patients (pts) receive first-line therapy (Rx) with FOLFOX [Folinic acid (FA), 5-fluorouracil (5-FU) and oxaliplatin (Ox)] + a biologic, making FOLFIRI [FA+ 5-FU+ irinotecan (Iri)] + bevacizumab (Bev) a common second-line Rx. This regimen has a median progression-free survival (PFS) of approximately 6 months (mo) and overall survival (OS) of 12 mo. Further gains are desperately needed. Trifluridine/tipiracil (FTD/TPI) is an oral combination Rx of a thymidine-based nucleoside analogue, FTD, and a phosphorylase inhibitor, TPI. FTD/TPI has a distinct mechanism of action from 5-FU and in preclinical models can overcome 5-FU resistance via DNA incorporation, base excision repair pathway and glycosylation responses to DNA damage. Further, there is an additive effect in combination with Iri. FTD/TPI was FDA approved for use in refractory metastatic CRC (mCRC) based on phase III RECOURSE trial. Phase I data showed combination of FTD/TPI, Iri and Bev to be safe, and an efficacy signal was seen in dose-expansion cohort (NCT01916447). A 12.5% response rate, 83.4 % disease control rate and PFS of 7.9 mo was achieved. As this study largely assessed refractory pts, one might expect a greater efficacy in Iri naïve pts. To test this hypothesis, we are conducting a multi-center phase II study of FTD/TPI, Iri and Bev as second-line Rx in mCRC pts. Methods: Eligible pts have mCRC and received first-line Ox based Rx. Rx to be given in 28-day cycles: Iri (180 mg/m2) and Bev (5 mg/kg) on D1 & 15, and FTD/TPI (25 mg/m2) twice daily on D2-6 & 16-20. Response assessment via CT/MRI to be done q8 wks (RECIST 1.1). Rx to continue until disease progression or unacceptable toxicity. The primary objective is to estimate PFS. Secondary objectives include ORR, OS, and safety. Final analysis to be done either 12 mo after enrollment of the final pt or once all pts have progression, whichever occurs earlier. A total of 40 pts to be accrued, and enrollment to start in January 2020. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Taiho Oncology, Inc.

TPS261 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. Trial accrual is anticipated across all US and Canadian cooperative groups.NCT#: 04068103. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: 04068103.

TPS464 Background: Neoadjuvant chemoradiation (CRT) followed by surgery is a standard approach for localized EGAC. Despite multimodality treatment, 5-year overall survival (OS) is less than 50%, with pathologic complete response (pCR) rates of 20%. Achievement of pCR is associated with an improved OS. We propose to use a novel combination of FTD/TPI and oxaliplatin as IC. We hypothesize that IC before CRT will increase the pCR rate in localized EGAC. Methods: This is an open-label, multicenter phase II trial. Patients (pts) with potentially resectable loco-regional EGAC are eligible. Pts. should have adequate organ function, ECOG performance status of 0 –1, age < 76 years, and endoscopic ultrasound-determined node-positive disease with any T-stage, or T3-T4a with any N stage. Pts. with T4b or M1 disease will be excluded. Pts. will receive three cycles of IC with FTD/TPI and oxaliplatin. Based on the maximum tolerated dose (MTD) observed in a phase I trial, FTD/TPI will be administered 35 mg/m² BID, days 1–5 every 14 days, with a fixed dose of oxaliplatin 85 mg/m² (day 1). Pts will then undergo concurrent CRT (standard radiation dose of 5040 cGY will be utilized) with weekly Carboplatin (AUC 2) and Paclitaxel (50 mg/m2) for 6 weeks followed by surgery. Our primary objective is to evaluate the pCR rate. The secondary objectives include evaluation of 2-year disease-free survival (DFS), 2-year OS, and assessment of toxicities of the IC. As a correlative endpoint, circulating tumor DNA level will be correlated with disease recurrence and metabolic response on PET CT. Assuming a historic pCR rate of 20% with standard CRT, 41 pts (enrollment of up to 45 pts accounting for non-evaluable pts) are needed to show a 15% increase in pCR with IC with 80% power at one-sided significance level of α = 0.1. In stage 1, n1= 22 evaluable pts will be enrolled. If there is 5 or more pCRs, an additional n2= 19 pts will be enrolled in stage 2. If 12 or more pCRs are observed in the total n = 41 evaluable pts, then the proposed treatment regimen will be considered promising for further study. We anticipate accrual over a 2-year period from 3 sites. Clinical trial information: NCT04097028.

11586 Background: Hand-foot skin reaction (HFSR) is the most common regorafenib adverse event. However, no intervention has demonstrated efficacy in preventing or palliating this adverse event, short of modulating the regorafenib dose. Methods: The Regorafenib Dose Optimization Study (ReDOS) was a randomized trial ( https://clinicaltrials.gov/ct2/show/NCT02368886 ); here we describe an a priori secondary analysis of ReDOS with the goal of assessing whether clobetasol 0.05% cream (a potent corticosteroid) applied to the palms and soles twice per day is more effective when prescribed pre-emptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the 1st 2 cycles of regorafenib. Results: Among 116 evaluable patients, 61 received pre-emptive clobetasol, and 55 reactive clobetasol. Baseline demographics were comparable between groups. During the 1st regorafenib cycle, 46% and 52% of patients developed HFSR with pre-emptive and reactive clobetasol, respectively (p = 0.52). However, during the 2nd cycle, 56% (of 47 total patients) and 80% (of 41 total patients), developed this toxicity with pre-emptive and reactive clobetasol, respectively (p = 0.02). Of note, during the 2nd cycle, rates of grade 1,2, and 3 HFSR were 40%, 11%, and 4% (pre-emptive) and 45%, 25%, and 10% (reactive) (p = 0.07). A sensitivity analysis to examine rates of no HFSR over all 2 regorafenib cycles showed that no HFSR occurred in 33% (of 61 total patients) with pre-emptive clobetasol versus 15% (of 55 total patients) with reactive clobetasol (p = 0.02). Patient-reported outcomes showed HFSR compromised activities of daily living, including getting dressed, preparing meals, walking, and even driving, with seemingly worse descriptive outcomes in patients who received reactive therapy. No adverse events from clobetasol were reported. Conclusions: Compared to reactive therapy, pre-emptive topical clobetasol might lessen regorafenib-induced HFSR. Clinical trial information: NCT02368886.

e15569 Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]

3032 Background: Irinotecan is a prodrug of the potent topoisomerase inhibitor SN-38. In animals, oral administration of irinotecan with the selective minimally absorbed P-gp inhibitor HM30181A increased the bioavailability of irinotecan. Oral administration of irinotecan may also increase the conversion to SN-38. Objectives: To determine the MTD and DLT of orally administered irinotecan in combination with HM30181A 15 mg on day 1 of a 21-day cycle. Additional objectives include determining the recommended phase 2 dose and the PK of irinotecan and SN-38. Methods: This was a phase 1 dose escalation study enrolling cohorts of 3-6 patients with advanced malignancies. Patients had Hb ≥9 gm/dL, ANC ≥ 1.5x109/L, platelets ≥ 100x109/L, adequate hepatic and renal function, ECOG 0-1 and were not homozygous for UGT1A1*28. Patients were administered HM30181A 15 mg and oral irinotecan 20, 40, 80, 120, 160, 200, 240, 280 and 320mg/m2. Results: Thirty male and female patients, mean age 60.9 (range 33-78) were enrolled into this ongoing study. The most common cancers were ovarian (6), colorectal (4), breast (4), endometrial (3), and pancreatic (3). The median number of cycles administered was 3 (range 1-9). Treatment-related Grade 3-4 AEs were experienced by 12 (40%) subjects. The most common were nausea 7 (23%), vomiting 6 (20%) and abdominal pain 3 (10%). Treatment-related SAEs were experienced by 6 (20%) patients (nausea or vomiting in 4 subjects). DLTs occurred in 2 patients at the 320 mg/m2 dose level (neutropenia and C. Difficile diarrhea) and additional patients are being enrolled at the 280mg/m2 dose level to define the MTD. Acute cholinergic diarrhea has not been observed. The best response was stable disease in 9/21 evaluable patients. PK at the three highest dose levels is summarized below. Conclusions: Oral administration of HM30181A in combination with irinotecan tablets results in pharmacologically active concentrations of SN-38. Confirmation of the MTD when dosed on a 21-day cycle is ongoing. Phase 2 studies are being planned. Clinical trial information: NTC02250157. [Table: see text]

4111Background: nal-IRI+5-FU/LV is effective for patients with mPAC after disease progression following gemcitabine-based therapy. The current study (NCT02551991) is a phase 1/2, open-label trial t...

3514Background: Pembrolizumab is approved for the treatment of adult and pediatric patients (pts) with previously treated MSI-H cancer regardless of tumor type or site. This approval was based in p...

611 Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.

TPS873 Background: Initial treatment of metastatic colorectal cancer (mCRC) involves a 5-fluorouracil based chemotherapy regimen, often in combination with anti-VEGF therapy. Upon disease progression, multiple studies have suggested a benefit for continued anti-VEGF therapy. There is increasing evidence that VEGF plays a role in cancer immune evasion. Targeting of inflammatory and immune checkpoints are attractive approaches to enhance the benefits of anti-VEGF therapy. The safety and activity of the anti-PD-L1 antibody atezolizumab with bevacizumab and with 5-FU, oxaliplatin, and bevacizumab have been recently reported; the combinations were well-tolerated and suggested clinical activity. Therefore, bevacizumab may increase the immunogenicity of colorectal cancers, and the combination of atezolizumab plus bevacizumab may be associated with clinically meaningful response rates and disease control. Furthermore, there may be candidate biomarkers that may identify those patients most likely to benefit from this combination. Methods: In this randomized, double-blind, multicenter, placebo-controlled phase II study, 135 patients with mCRC will be randomized 2:1 to receive capecitabine/bevacizumab/atezolizumab or capecitabine/bevacizumab/placebo. Patients with prior PD-L1/PD-1 therapy are ineligible. Primary and secondary efficacy will be conducted using ITT analysis. Safety analyses will include all randomized patients who receive at least one dose of study treatment. The primary objective is PFS. The secondary objectives are ORR, OS, safety, and tolerability. The primary comparison will be superiority of the active treatment for the PFS endpoint, atezolizumab versus placebo testing at 1-sided α = 0.1 (log rank test). A PFS hazard ratio of 0.618 (active treatment versus placebo) is detectable with 86% power (1 sided α = 0.1). No interim analyses for futility or efficacy will be conducted. A subset analysis will be performed in the microsatellite-high patients looking at potential differences in PFS and OS. Trial is active and currently recruiting patients. Clinical trial information: NCT02873195.

834 Background: Cetuximab is a chimeric IgG1 anti-EGFR monoclonal antibody approved in RAS-wt metastatic colorectal cancer (mCRC). Pre-clinical data have suggested that cetuximab triggers immunogenic cell death and support an immunologic basis of activity. Small clinical data sets demonstrate that EGFR-based therapy preferentially increases TILs in colorectal hepatic metastases. This Phase Ib/II study was designed to assess the safety and clinical activity of cetuximab and pembrolizumab in metastatic colorectal cancer. Methods: Eligible pts were those with RAS-wt mCRC, ECOG performance status (PS) 0-2, with at least 1 prior line of therapy for advanced stage disease, and no prior treatment with an anti-EGFR antibody. The phase Ib study was designed as a safety lead-in with a de-escalation design. Pembrolizumab was administered at a fixed dose of 200 mg q3week with standard cetuximab dosing (400 mg/m2 loading dose, followed by 250 mg/m2 weekly). DLTs were defined as any ≥ grade 3 clinically significant toxicity which is possibly related and occurs within the first 6 weeks of therapy. For rash and hypomagnesemia only ≥ grade 4 toxicities were considered DLTs. Correlative serial biopsies were performed at baseline and at 9 weeks. Results: 9 patients, ages 33-73, were enrolled onto the Phase Ib study between 8/10/16 and 11/2/16. No DLTs were observed. The most common AEs of any cause observed were xerosis, dermatitis acneiform rash, hypomagnesemia, vomiting, and fatigue. ≥ Grade 3 toxicities were uncommon, but included hypomagnesemia (3), rash (1), urticaria (1), hypocalcemia (1), alk phos elevation (1), and ascites (1). 6/9 patients achieved stable disease lasting ≥ 16 weeks. Conclusions: The combination of cetuximab and pembrolizumab is well-tolerated in this study and can be administered at full dosages. Though hypomagnesemia appears prominent, no additional emergent AEs have been observed during or following the DLT period. The associated ongoing phase II study will enroll an additional 33 patients to assess the true efficacy of this regimen with dual primary endpoints of ORR and 6 month PFS. Clinical trial information: NCT02713373.

716 Background: 15-20% of patients with locally advanced rectal adenocarcinoma (LARC) achieve a pathologic complete response (pCR) following neoadjuvant chemoradiation (nCRT). The role of adjuvant chemotherapy has been questioned. Methods: Patients with rectal cancer receiving nCRT in the National Cancer Data Base (NCDB) 2006-2013 data set were evaluated. The primary outcome was overall survival (OS). The association between OS and patient characteristics were examined using multivariable Cox regression models. Results: 2,903 patients were identified who achieved a pCR. The median follow up was 43.2 months. 2,102 received nCRT and 789 received nCRT + adjuvant chemotherapy. Factors significantly associated with OS included age (p

759 Background: Refractory metastatic colorectal cancer patients (mCRC) have a poor prognosis with median survival of 4-6 months. Nintedanib is a TKI which inhibits VEGFR, PDGFR, and FGFR with preclinical efficacy in bevacizumab resistant CRC. This phase I/II study sought to evaluate the recommended phase II dose (RP2D) and efficacy of nintedanib and capecitabine in refractory mCRC patients. Methods: Key eligibility criteria included histologically proven mCRC, ECOG PS of 0 or 1, progression/intolerance to a fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR therapy for RAS wt patients. Prior regorafenib, uncontrolled hypertension ( ≥ 160/90), recent clinically significant thrombosis/hemorrhage, or prior intolerance to capecitabine were exclusionary. Doses were escalated across 2 planned dose levels (DL) in a standard 3+3 design, with escalating doses of capecitabine. DLT observation window was the first 3 weeks after dosing. The primary endpoint was establishment of the RP2D. Results: 10 patients were enrolled across 2 dose levels. 1 patient withdrew consent and was replaced. 5 (50%) were PS 0. No grade 4 or 5 AEs were observed. No DLTs were observed. 2/10 (20%) of patients experienced a grade 3 AE, including hyperbilirubinemia (10%), AST elevation (10%), diarrhea (10%), dehydration (10%), and weakness (10%). The most common treatment-related AEs included palmar-plantar eythrodysesthesia (PPE) (50%), diarrhea (40%), stomatitis (30%), nausea (20%), vomiting (20%), and fatigue (20%). The RP2D was determined to be capecitabine 1000 mg/m2 divided bid and nintedanib 200 mg bid. PK data will be presented. Conclusions: Treatment was well tolerated. Most of the observed AEs were grade 1 or 2, without a marked difference between DLs. PPE was readily managed with dose adjustments. The phase II study is ongoing at the RP2D. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Boehringer Ingelheim Pharmaceuticals, Inc. Clinical trial information: NCT02393755.

TPS3630Background: Regorafenib is an oral multikinase inhibitor that blocks several protein kinases involved in angiogenesis and oncogenesis. It was recently shown to provide a survival benefit in ...

11016Background: P, a VEGFR TKI, is approved for advanced STS based on median PFS (mPFS) in the absence of CR. Endoglin is a receptor expressed on tumor vessels that is overexpressed in certain STS...

728 Background: Anorectal squamous cell carcinomas (SCCs) are rare in the United States with < 10,000 cases annually. Uncommonly, patients present with stage IV disease or recurrence after definitive therapy. Limited options exist for these patients. We queried Roswell Park Cancer Institute (RPCI) patient records to determine systemic treatments utilized and outcomes for these patients. Methods: Patients with anal or rectal SCC between 1/1/99 and 7/1/2014 were identified via the cancer registry. 65 patients were flagged for review. From manual review, 31 patients received treatment at RPCI and were deemed evaluable. Demographic data, histology, staging, treatment history, time receiving any specific therapy and response assessment were abstracted from the records. Results: Of the 31 patients, 45% were male, 55% female. Primary tumors were anorectal (84%) or rectal (16%) in origin. 5(16%) presented with rectal SCC. Sites of metastatic disease were most commonly identified as lymph nodes (48%), liver (35) or lung (16%). At the time of analysis 5 (16%) were alive, with 3 (10%) disease free. Median overall survival (OS) was 44.1 months (95% CI, 28.9 - 62.6). The most commonly utilized chemotherapy regimens were 5-fu/cisplatin (n = 22 patients) and taxol (n = 10). Mean time on therapy was 4 months for 5-fu/platinum doublets (n = 24), 4 months for taxanes/platinum combinations (n = 6), 3.4 months for anti-EGFR containing regimens (n = 7) and 2.43 months for taxane monotherapy (n = 10). The most common reasons for discontinuation of therapy were progressive disease (47%) or patient choice (15%). Conclusions: New therapies are desperately needed for advanced anorectal SCCs. At present, 5-FU/cisplatin is the best endorsed and most frequently utilized regimen. Consistent with other reports, platinum doublets and anti-EGFR targeted therapies appear to confer significant benefits, within the realm of 5-fu/cisplatin, with single agent taxanes appearing to have lesser activity. Small absolute patient numbers and lack of reliable response measurements preclude firm conclusions. Future clinical trials to evaluate systemic therapies in advanced anorectal SCCs, including anti-EGFR regimens, are warranted.

11107 Background: Several distinct cancers are caused by human papillomavirus (HPV)- including squamous cell carcinomas of the cervix (CSCC), anal canal (ASCC), and oropharynx (OSCC). Importantly, ...

3519 Background: Squamous cell anal carcinoma is a rare, HPV-associated malignancy accounting for 2% of digestive system cancers. Usually these malignancies are detected early and successfully mana...

245 Background: The rarity of NETs can limit clinical trial accrual to develop new therapies. Given fewer approved treatments, a better understanding of underlying biology is critical to development of and assignment of patients (pts) to clinical trials. Methods: Pts with NETs (excluding small/large cell lung cancer) of all grades at FCCC were enrolled onto a prospective IRB approved protocol that utilized an NGS platform to detect somatic mutations (SM) in 50 cancer-related genes (Cancer Code) on archived tissue from primary or metastatic sites. Genes tested included ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNA11, GNAQ, GNAS, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, SMAD4, SMARCB1, SMO,SRC, STK11, TP53 and VHL. Review of pathology specimens for grade and Ki -67 was also performed. Results: Thirty-nine pts (median age 59 y, males 46%) were enrolled from October 2013 to July 2014. Gene profiling results are available on thirty-five pts. Ki-67 score was reviewed for 31/35 tumors. 6 (20%) pts had high grade (HG) tumors (Ki-67 > 20%) and 25 (80%) had low/intermediate grade (LIG) tumors (Ki-67 ≤20%). Thirteen (37%) pts were found to have SMs and 22 (63%) did not, with 4 (12%) pts’ tumors having >1 SMs (2 HG and 2 LIG tumors). Incidence of SM was 41% (12/29) in Caucasians, 16% (1/6) in other races, 46% (6/13) in smokers and 30% (6/20) in non-smokers. Incidence of SM was 24% (6/25) in LIG NETs and 84% (5/6) in the HG NETs. Among HG tumors, 66% (4/6) harbored TP53 gene mutation and 33% (2/6) were BRAF mutation positive. Conclusions: Tumor-specific mutations are seen in a minority of low grade NETs but are common in high grade tumors. Interestingly, no mutations were identified in pts with unknown primary. Analysis of clinical outcomes based on treatment received is ongoing to assess for possible prognostic/therapeutic implications of these mutations. [Table: see text]

603 Background: Anal squamous cell carcinoma (Anal SCC) is a rare, HPV-associated malignancy accounting for 2.4% of digestive system cancers. In most cases, these malignancies are detected in the early stages and successfully managed with chemoradiation therapy. Uncommonly, these cancers recur or present with metastases. In this setting, cisplatin and 5-fluorouracil represent the only endorsed regimen. Once beyond standard therapy, few therapeutic options exist for those patients with aggressive disease. The purpose of this study is to identify other novel, potential targets and therapeutic options for this disease, utilizing a multiplatform approach. Methods: 206 anal SCC specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). 6 cases were documented as positive for HPV or HIV; status was not provided on the remaining 200. Results: Key results are shown in the table below, shown as percent change/total cases. Conclusions: Multiplatform tumor profiling identified a low incidence of gene mutations. Protein expression aberrations identified potential treatment options not routinely considered, such as topoisomerase inhibitors and taxanes. Mutations in PIK3CA, Akt1, and FBXW7 as well as PTEN loss indicate potential for targeting the PI3 kinase pathway. Additionally, immunomodulatory agents may be a therapeutic option, based on PD-1 expression levels. Targeting the ErbB-family receptors, namely with anti-EGFR agents or newer generation pan-HER - inhibitors, may represent another option, given EGFR and HER2 amplification as well as EGFR overexpression. It should be mentioned that differences in anal carcinomas whose etiology is of viral origin may present different treatment options based on the driver mutations. [Table: see text]

e17624 Background: NGS genomic testing technologies are rapidly entering routine oncology practice. GC are critical to bridging the gap between genomic medicine and patient care, but may be inadequ...

e17635 Background: The potential to one day tailor all cancer treatments to a tumor’s genomic profile is an emerging reality due to the commercial availability of NGSGT. While healthcare providers ...

11092 Background: The use of molecular targeted therapeutic agents may require the application of sophisticated diagnostic technologies for patients’ selection. Next generation DNA sequencing (NGS) has the ability to identify genetic alterations (GA) including mutations, copy number alterations, insertions/deletions, and rearrangements in tumor specimens. We sought to evaluate patients with advanced and refractory epithelial tumors to detect potentially actionable molecular abnormalities. Therapeutic intervention driven by GA findings was determined solely by the patient’s treating physician. Methods: Tumor samples from 77 patients ≥ 18 years old with any solid malignancy were sequenced. NGS of 186 genes was performed by FoundationOne through funding from Foundation Medicine using archival or newly acquired tumor tissue. Results: Seventy-four patients had specimens with adequate material for DNA extraction and analysis. Characteristics: 74% female, median age 55 years (19-82). Tumor sites included inflammatory breast (50%), colon (12%), unknown primary (5%) and other (33%). At least one genetic alteration was seen in 71 (96%) patients. The most common GA included mutations in 65 (60%) samples revealing TP53 (32%), KRAS (10%), PIK3CA (8%), and APC (6%) and amplifications in 38 (35%) samples which included MYC (18%), MCL1 (14%), CCND1 (12%), and ERBB2 (7%). Copy number loss (4%), fusion (1%) and deletions (2%) were also discovered. An actionable GA was seen in 46 of 74 patients successfully tested (62%), with 54% of GAs being amplifications and 43% mutations. Patients had a median of 3 GA (range 0-7). One patient with anal cancer had a concomitant PIK3CA mutation and amplification. NGS in association with immunohistochemistry helped identify site of origin for one patient with an occult primary. Conclusions: NGS identified GAs in the majority of patients with advanced epithelial cancers, including actionable abnormalities in a large fraction of this heterogeneous population. NGS shows promise in the diagnostic evaluation of advanced malignancies. Future studies should include the potential prognostic implications of genomic-driven personalized therapy.